Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3 protease Senp3.
The stabilization and subcellular localization of the p19(Arf) tumor suppressor protein and the SUMO-2/3 deconjugating protease Senp3 each depend upon their binding to the abundant nucleolar protein nucleophosmin (Npm/B23). Senp3 and p19(Arf) antagonize each other's functions in regulating the SUMOylation of target proteins including Npm itself. The p19(Arf) protein triggers the sequential phosphorylation, polyubiquitination and rapid proteasomal degradation of Senp3, and this ability of p19(Arf) to accelerate Senp3 turnover also depends on the presence of Npm. In turn, endogenous p19(Arf) and Senp3 are both destabilized in viable Npm-null mouse embryo fibroblasts (that also lack p53), and reintroduction of the human NPM protein into these cells reverses this phenotype. NPM mutants that retain their acidic and oligomerization domains can re-stabilize both p19(Arf) and Senp3 in this setting, but the nucleolar localization of NPM is not strictly required for these effects. Knockdown of Senp3 with shRNAs mimics the antiproliferative functions of p19(Arf) in cells that lack p53 alone or in triple knock-out cells that lack the Arf, Mdm2 and p53 genes. These findings reinforce the hypothesis that the p53-independent tumor suppressive functions of p19(Arf) may be mediated by its ability to antagonize Senp3, thereby inducing cell cycle arrest by abnormally elevating the cellular levels of SUMOylated proteins.
Kuo
Mei-Ling
ML
Howard Hughes Medical Institute, Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
den Besten
Willem
W
Thomas
Mary C
MC
Sherr
Charles J
CJ
D000818:Animals; D002466:Cell Nucleolus / Q000378:metabolism*; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D003546:Cysteine Endopeptidases; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D000090243:Nucleophosmin; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; C515972:SUMO2 protein, mouse; D025841:Small Ubiquitin-Related Modifier Proteins; C117908:Sumo3 protein, mouse; D014452:Ubiquitins; D000090243:Nucleophosmin; D025821:Polyubiquitin; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; C492190:Senp3 protein, mouse; D046988:Proteasome Endopeptidase Complex